Treatment of hepatitis C virus infection_ is it time for the internist to take th...

Treatment of Hepatitis C Virus Infection:Is It Time for the Internist to Take the Reins?

Shyam Kottilil,MD,PhD;Mary Wright,MD,MPH;Michael A.Polis,MD,MPH;and Henry Masur,MD

F or the?rst time since the identi?cation of hepatitis C

virus(HCV)in1988,communitywide eradication of HCV infection seems possible.With the U.S.Food and Drug Administration’s approval in late2013of simeprevir and sofosbuvir,2direct-acting oral anti-HCV drugs,the time has come to launch major initiatives to reduce the effect of this infection on individuals and on our commu-nities.Who should lead the charge to initiate and manage treatment:subspecialists,internists,or both?

Globally,230million persons are infected with HCV, including2.7to3.9million persons in the United States (1,2).Spontaneous resolution occurs in only20%of HCV-infected individuals,and many chronically infected persons progress to cirrhosis(20%over25years)and de-velop hepatocellular carcinoma(20%of cirrhotic patients). Over the past2decades,HCV infection was treated?rst with parenteral interferon-?alone,then with pegylated interferon-?plus oral ribavirin,and more recently with oral boceprevir or telaprevir added to pegylated interferon plus ribavirin.Although each successive regimen incremen-tally reduced long-term complications of HCV infection, the regimens were lengthy(24to48weeks),were only modestly effective,and were poorly tolerated(often be-cause of depression and anemia and leukopenia).Thus, fewer than10%of eligible patients have received treatment (3,4).

In addition to simeprevir and sofosbuvir,many direct-acting oral anti-HCV drugs are in late development stages. Direct-acting regimens without interferon and ribavirin, administered for only6to12weeks,have yielded response rates greater than90%with excellent tolerability and safety (5–7).These results are stunning triumphs for translational medicine if further trials con?rm and extend these?nd-ings,although much remains to be learned about speci?c host,viral,and drug factors that in?uence treatment outcomes.The Infectious Diseases Society of America and the American Association for the Study of Liver Dis-eases have jointly released recent dynamic online clinical guidance for providers that accommodates rapid updates (0c4326d8fd0a79563c1e72e1).

Internists have long played a unique and critical role on the forefront of HCV infection care by counseling, testing,and identifying patients with this disease.How-ever,for treatment,most patients have been referred to hepatologists.If a cure for and communitywide eradication of HCV infection become realistic goals,will there be enough subspecialists to treat all infected patients?Is subspecialty expertise necessary for managing all HCV-infected patients?

Overseeing treatment of HCV infection in2to4mil-lion persons in the United States would probably over-whelm the country’s1800hepatologists.Even if all7000 practicing infectious disease subspecialists in the United States focused on this disease,it would not be suf?cient. The subspecialist workforce would be overtaxed even if the 2to4million persons eligible for treatment were priori-tized to begin therapy over5to10years.

As treatment of HCV infection becomes more straightforward and does not require invasive diagnostic tests,such as liver biopsy,internists can and should take a more active role in treating most patients except those with advanced cirrhosis.Subspecialty referral should be unnec-essary for many HCV-infected persons,especially those without advanced?brosis,severe extrahepatic manifes-tations of HCV infection,or substantial comorbid conditions.

Once criteria are developed for subspecialist referral and prioritization of treatment,internists should be able to quickly develop the expertise to screen for relevant HCV-drug-resistance mutations,assess stage of liver disease,and determine which patients require subspecialist care and which patients with uncomplicated HCV infection they can treat using breakthrough drugs.Thus,internists should be leaders in this unprecedented opportunity to cure this chronic and morbid viral disease.

Internists,subspecialists,and public health authori-ties will need to work together to address barriers to adherence—as well as such issues as emergence of viral resistance—and the effect of reinfection,cost,and access (8).Finding funds to launch and operationalize widespread testing programs,persuade asymptomatic persons to be tested,link infected individuals to stable medical care,pro-vide psychosocial support to patients with special needs, and persuade patients to receive therapy for an infection that often remains completely asymptomatic will pose con-siderable challenges.

We can learn from our25years of experience with HIV and AIDS.Our successes in reducing the effect of this infection in the United States have had some notable vic-tories,but far more success is needed in important areas. Only25%of HIV-infected patients are receiving stable care and have suppressed viral loads(9),which is sobering.

However,the HIV and HCV infection epidemics have some prominent differences.HIV requires lifelong therapy. In contrast,the ability to cure a life-threatening HCV in-fection with only6to12weeks of therapy is likely to make programmatic successes far easier in this condition than in HIV and AIDS.Internists must be leaders in educating all stakeholders about these opportunities and in transition

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ensuring the from patient identi?cation to patient cure and community eradication(7).

Even if testing and linkage to care were readily avail-able for all infected persons,the cost of acquisition for the new direct-acting oral anti-HCV drugs is sobering. The current market price for1recommended regimen, simeprevir plus sofosbuvir for12weeks,is$150000(10). Whether this price is cost-effective,let alone affordable or reasonable,requires careful analysis.

Patients with early disease could be counseled and monitored for years instead of being treated immediately. However,although market competition may decrease drug acquisition costs and multidrug combination regimens may allow progressively shorter regimens,it will be impor-tant to identify patients who need treatment sooner rather than later and thus those for whom current drug costs are warranted.

Treatment of HCV infection has entered a new era in which the cure of individual patients is eminently feasible and communitywide eradication is conceivable.A robust debate is accelerating about whom and when to treat and what fraction of our resources should be devoted to HCV infection.As advocates for their patients and communities, internists must have a strong voice in this debate to assure that those patients in imminent danger of HCV infection–related illness can access these promising drugs. The time for internists to embrace delivering therapeutic interventions for HCV infection in their practices is now. From the Laboratory of Immunoregulation,National Institute of Allergy and Infectious Diseases,and National Institutes of Health Clinical Cen-ter,National Institutes of Health,Bethesda,Maryland.

Financial Support:By the intramural program of the National Institutes of Health Clinical Center and National Institute of Allergy and Infec-tious Diseases.

Disclosures:Authors have disclosed no con?icts of interest.Forms can be viewed at 0c4326d8fd0a79563c1e72e1/authors/icmje/Con?ictOfInterestForms .do?msNum?M14-0741.Corresponding Author:Henry Masur,MD,Critical Care Medicine Department,National Institutes of Health Clinical Center,10Center Drive,Room2C145,Bethesda,MD20892.

Current author addresses and author contributions are available at www 0c4326d8fd0a79563c1e72e1.

Ann Intern Med.2014;161:443-444.doi:10.7326/M14-0741 References

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2.Thomas DL.Global control of hepatitis C:where challenge meets opportu-nity.Nat Med.2013;19:850-8.[PMID:23836235]doi:10.1038/nm.3184

3.Alavi M,Raffa JD,Deans GD,Lai C,Krajden M,Dore GJ,et al.Continued low uptake of treatment for hepatitis C virus infection in a large community-based cohort of inner city residents.Liver Int.2013.[PMID:24164865]doi: 10.1111/liv.12370

4.McGowan CE,Monis A,Bacon BR,Mallolas J,Goncales FL,Goulis I,et al.

A global view of hepatitis C:physician knowledge,opinions,and perceived bar-riers to care.Hepatology.2013;57:1325-32.[PMID:23315914]doi:10.1002/ hep.26246

0c4326d8fd0a79563c1e72e1witz E,Mangia A,Wyles D,Rodriguez-Torres M,Hassanein T,Gordon SC,et al.Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med.2013;368:1878-87.[PMID:23607594]doi:10.1056 /NEJMoa1214853

6.Sulkowski MS,Gardiner DF,Rodriguez-Torres M,Reddy KR,Hassanein T,Jacobson I,et al;AI444040Study Group.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med.2014; 370:211-21.[PMID:24428467]doi:10.1056/NEJMoa1306218

7.Kohli A,Osinusi A,Sims Z,Nelson A,Meissner EG,Barrett LL,et al. Directly acting triple-drug anti-HCV therapy induces complete virologic response with a six-week regimen:a proof of concept phase2a cohort 0c4326d8fd0a79563c1e72e1ncet.2014. [Forthcoming].

8.Murata G,Deming P,Kalishman S,Dion D,et al.Outcomes of treatment for hepatitis C virus infection by primary care providers.N Engl J Med.2011; 364:2199-207.[PMID:21631316]doi:10.1056/NEJMoa1009370

9.Mugavero MJ,Amico KR,Horn T,Thompson MA.The state of engage-ment in HIV care in the United States:from cascade to continuum to control. Clin Infect Dis.2013;57:1164-71.[PMID:23797289]doi:10.1093/cid/cit420 10.Hoofnagle JH,Sherker AH.Therapy for hepatitis C—the costs of success [Editorial].N Engl J Med.2014;370:1552-3.[PMID:24725236]doi:10.1056 /NEJMe1401508

Ideas and Opinions Treatment of Hepatitis C Virus Infection

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Current Author Addresses:Dr.Kottilil:Laboratory of Immunoregula-tion,National Institute of Allergy and Infectious Diseases,National In-stitutes of Health,9000Rockville Pike,Building10/11N204,Bethesda, MD20892.

Dr.Wright:Division of Clinical Research,National Institute of Allergy and Infectious Diseases,National Institutes of Health,8West Drive, MSC2665,Building15B1,Room0204,Bethesda,MD20892.

Dr.Polis:Division of Clinical Research,National Institute of Allergy and Infectious Diseases,National Institutes of Health,Room1118, 6700B Rockledge Drive,Bethesda,MD20892.

Dr.Masur:Critical Care Medicine Department,National Institutes of Health Clinical Center,10Center Drive,Room2C145,Bethesda,MD 20892.Author Contributions:Conception and design:S.Kottilil,M.A.Polis, H.Masur.

Analysis and interpretation of the data:S.Kottilil,M.A.Polis,H.Masur. Drafting of the article:S.Kottilil,M.Wright,M.A.Polis,H.Masur. Critical revision of the article for important intellectual content: S.Kottilil,M.Wright,M.A.Polis,H.Masur.

Final approval of the article:S.Kottilil,M.A.Polis,H.Masur. Provision of study materials or patients:S.Kottilil.

Statistical expertise:S.Kottilil.

Obtaining of funding:S.Kottilil,H.Masur.

Administrative,technical,or logistic support:S.Kottilil,H.Masur. Collection and assembly of data:S.Kottilil.

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